| First Author | West E | Year | 2017 |
| Journal | J Cell Sci | Volume | 130 |
| Issue | 18 | Pages | 3050-3059 |
| PubMed ID | 28760925 | Mgi Jnum | J:247312 |
| Mgi Id | MGI:5915111 | Doi | 10.1242/jcs.205484 |
| Citation | West E, et al. (2017) The cholesterol ester cycle regulates signalling complexes and synapse damage caused by amyloid-beta. J Cell Sci 130(18):3050-3059 |
| abstractText | Cholesterol is required for the formation and function of some signalling platforms. In synaptosomes, amyloid-beta (Abeta) oligomers, the causative agent in Alzheimer's disease, bind to cellular prion proteins (PrPC) resulting in increased cholesterol concentrations, translocation of cytoplasmic phospholipase A2 (cPLA2, also known as PLA2G4A) to lipid rafts, and activation of cPLA2 The formation of Abeta-PrPC complexes is controlled by the cholesterol ester cycle. In this study, Abeta activated cholesterol ester hydrolases, which released cholesterol from stores of cholesterol esters and stabilised Abeta-PrPC complexes, resulting in activated cPLA2 Conversely, cholesterol esterification reduced cholesterol concentrations causing the dispersal of Abeta-PrPC complexes. In cultured neurons, the cholesterol ester cycle regulated Abeta-induced synapse damage; cholesterol ester hydrolase inhibitors protected neurons, while inhibition of cholesterol esterification significantly increased Abeta-induced synapse damage. An understanding of the molecular mechanisms involved in the dispersal of signalling complexes is important as failure to deactivate signalling pathways can lead to pathology. This study demonstrates that esterification of cholesterol is a key factor in the dispersal of Abeta-induced signalling platforms involved in the activation of cPLA2 and synapse degeneration. |
